There is little or no data examining the association between either pain or the use or misuse of opioid analgesic with adherence to antiretroviral medications (ARVs) among HIV-infected adults. We interviewed a community-based cohort of HIV-infected indigent adults prescribed antiretroviral medications (ARVs) quarterly to examine the association between (1) pain, (2) receipt of opioid analgesics, and (3) opioid analgesic misuse with self-reported ARV adherence. Of 281 participants, most (82.5 %) reported severe or moderate pain, half (52.4 %) received a prescription for opioids, and one quarter (24.6 %) misused opioid analgesics. Most (71.9 %) reported >90 % ARV adherence. In a GEE model, neither pain (unadjusted OR 1.14, CI 0.90–1.45) nor prescription of opioid analgesics (unadjusted OR 1.11, CI 0.84–1.49) were significantly associated with ARV adherence. Misuse of opioid analgesics was associated with incomplete adherence (AOR 1.42, CI 1.09–1.86). Individuals who misuse opioid analgesics, like those who use illicit substances, may have difficulty adhering to medication regimens.